Since the discovery of the cardiac hormone ANP by DeBold and coworkers in 1981, the field of natriuretic peptides has significantly advanced with translation of new knowledge to the clinical practice of heart failure (HF). This new knowledge has underscored the importance of cardio-renal mechanisms that contribute to optimal cardiovascular homeostasis. Work by others and the applicants have also established direct myocardial actions broadening their therapeutic potential beyond renal mechanisms. Most recently, BMP has been evaluated and approved as an intravenous therapy for symptomatic HF and as a diagnostic aid in HF. With the availability of new technologies, this field can be further advanced to provide additional knowledge with application to human cardiovascular disease. The broad objective of our application in experimental and human HF is to advance the cardiac peptide BNP as a novel therapeutic strategy for cardio-renal protection in progressive HF. The special focus on BNP is based upon significant progress during the current HL36634 funding period that recognizes the greater natriuretic action of BNP in HF compared to ANP and also importantly its anti-aldosterone and anti-fibrotic properties. Work by the applicants has also established unique hemodynamic actions in HF in which BNP enhances diastolic function and reduces left ventricular end systolic and diastolic volumes. Further, preliminary studies in advanced human HF support the possible presence of altered forms of circulating BNP with reduced biological action. Our specific goal is therefore to delay the progression of HF with novel chronic BNP based therapy through cardio-renal mechanisms. We will take a physiologic, genomic and proteomic approach in studies in large animal models of experimental HF and early and late stage human HF. Our Specific Aims are as follows: Aim 1: To establish that chronic BNP delays the progression of experimental HF in the presence and absence of mineralocorticoid excess. Aim 2: To determine that the anti-fibrotic action of chronic BNP therapy also is independent of myocardial load. Aim 3: To determine the presence of altered forms of circulating BNP in early and late stage human HF. Aim 4: To determine the biological actions and binding properties of altered forms of circulating BNP in human HF in vitro and in vivo.